Methylphenidate (Ritalin) is a psychostimulant drug approved for treatment of ADHD or attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It was first licensed by the FDA in 1955 for treating ADHD, prescribed from 1960, and became heavily prescribed in the 1990s, when the diagnosis of ADHD itself became more widely accepted. It is available worldwide with different brand names like Concerta®, Daytrana®, Metadate CD®, Metadate® ER, Methylin®, Quillivant™ XR, Ritalin LA®, Ritalin-SR®, Ritalin®. Here 2-phenyl-2-(piperidin-2-yl) acetamide is key intermediate to prepare methylphenidate or its salts thereof.

Until the introduction of d-threo methylphenidate hydrochloride, dexmethylphenidate hydrochloride, Focalin®) in 2002, all marketed forms of methylphenidate contained a 50:50 racemic mixture of d-threo methylphenidate and 1-threo methylphenidate in the form of the hydrochloride salt. In 2007, a transdermal patch containing racemic dl-threo methylphenidate (Daytrana®) was approved by the FDA.
U.S. Pat. No. 2,957,880 describes a sequence involving the resolution of the amide derivative of the corresponding erythro isomer, conversion to the threo isomer, followed by the hydrolysis of the amide to the corresponding acid in isolated form, and esterification of the resulting acid with methanol to give methylphenidate.

Mixture of threo and erythro isomer of amide
Patrick, K. S., J. Med. Chem. 24:1237-1240 (1981), discloses the process, according to disclosure, erythro- and threo-dl-2-(4-methoxyphenyl)-2-(2′-pyridyl) acetamide hydrochloride is dissolved in glacial acetic acid and PtO2 is added into it. Thus, conversion from pyridine to piperidine ring takes place in hydrogen pressure. After evaporation the obtained oil is dissolved in methanol, treated with Norite and filtered and then excess of diethyl ether-HCl is added. The solvent is evaporated to obtain erythro- and threo-dl-2-(4-methoxyphenyl)-2-(2′-piperidyl)acetamide hydrochloride in 72% yield. Further it is treated with hydrochloric acid to obtain erythro- and threo-dl-2-(4-methoxyphenyl)-2-(2′-piperidyl)acetic acid hydrochloride. Alternatively, erythro- and threo-dl-2-(4-methoxyphenyl)-2-(2′-piperidyl)acetamide hydrochloride is treated with 50% potassium hydroxide for 4 days until an aliquot contained no more than 5% erythro isomer. The mixture is cooled and crystallized by ethyl acetate to give 95+% threo isomer and 53% yield. Then it is followed by treatment of 48% hydrobromic acid to obtain hydrobromide salt of corresponding threo-dl-2-(4-hydroxyphenyl)-2-(2′-piperidyl) acetic acid having 95+% threo isomer and 94% yield. The obtained white crystals are treated with methanol-HCl followed by evaporation of solvent and recrystallized with acetone-diethyl ether to get methylphenidate hydrochloride having 73% yield. The overall yield is just around 26% from erythro- and threo-dl-2-(4-methoxyphenyl)-2-(2′-pyridyl) acetamide hydrochloride, which is industrially not advantageous.
Synthetic methods for preparing racemic mixtures of threo- and erythro-α-phenyl-2-piperidineacetamides as raw materials for the preparation of threo-methylphenidate are described in U.S. Pat. Nos. 2,507,631; 2,838,519; 2,957,880 and 5,936,091; and in J. Med. Chem., 39, 1201-1209 (1996). These methods disclose reduction of the pyridine ring to a piperidine ring by hydrogenation on PtO2 Pt/C catalyst in glacial acetic acid as a solvent. The reaction takes about 26 hours for the completion.

U.S. Pat. No. 7,459,467 describes the preparation of α-phenyl-α-piperidyl-2-acetamide by treating α-phenyl-α-pyridyl-2-acetamide with 0.1N perchloric acid in acetic acid, Pd/C and alcohol as reaction media under 12-15 Kg/cm2 hydrogen pressure at 45-50° C. for 15-18 hours. The catalyst is removed by filtration. The filtrate is concentrated under reduced pressure followed by basifying with aqueous sodium hydroxide solution to precipitate α-phenyl-α-piperidyl-2-acetamide. The patent is silent or not disclosing the conversion of α-phenyl-α-piperidyl-2-acetamide to methylphenidate hydrochloride. The patent discloses preparation of methylphenidate free base from α-phenyl-α-pyridyl-2-methyl acetate by using same reaction condition, reagents and solvent for the reduction as mentioned above. The preparation of methylphenidate hydrochloride from methylphenidate obtained in 78%; hence 22% yield loss is uneconomic and isolation of methylphenidate and then converson to corresponding hydrochloride salt adds more unit operations and yield loss as well. The above process for the preparation of α-phenyl-α-piperidyl-2-acetamide is not feasible at large scale because it uses 0.1N perchloric acid which is unsafe, process needs hastelloy autoclave and also has the high pressure 12-15 Kg/cm2 which is not safe at large volume in autoclave. The process involves tedious and lengthy operation for isolation of α-phenyl-α-piperidyl-2-acetamide. Volumes of solvents are also 11-15 times of input; hence the process is also not environment friendly.
U.S. Pat. No. 7,229,557 describes the esterification of dl-ritalinic acid in about 20 molar equivalents of methanol saturated with hydrogen chloride gas under reflux. From the reaction, dl-threo methylphenidate hydrochloride was obtained in 37%yield.
U.S. Patent Application 2010/0179327 describes the preparation of amino acid esters such as methylphenidate. The application describes the reaction of threo-α-phenyl-α-(2-piperidinyl)acetic acid [threo 99.51%: erythro 0.49%], methanolic HCl, and trimethyl orthoacetate with heating at reflux to form methylphenidate in 69.8% yield. As per the disclosure, 69.8% yield of methylphenidate is not viable from the industrial point view, even after taking 99.51% pure threo-α-phenyl-α-(2-piperidinyl)acetic acid.
PCT application no. 2011/067783 discloses process for the preparation of methylphenidate hydrochloride by reacting α-phenyl-α-piperidyl acetamide with 20% aqueous hydrochloric acid solution and reflux for 2-6 hours. The reaction mixture is cooled and diluted by water to get clear solution followed by extracting with dichloromethane. The layers are separated and pH of aqueous layer is adjusted by adding sodium hydroxide to get threo α-phenyl-α-piperidyl-2-acetic acid in 88.6% yield having isomeric purity [threo 99.9%: erythro 0.1%]. It means the process using very pure α-phenyl-α-piperidyl acetamide to prepare pure threo α-phenyl-α-piperidyl-2-acetic acid. Thus obtained corresponding acid is converted to methylphenidate hydrochloride by treating with thionyl chloride and methanol at temperature below 10° C. The reaction mixture is kept under stirring over night at room temperature followed by distillation of methanol under reduced pressure and then cooled to 10° C. Water and ethyl acetate is added into the residue under constant stirring. The pH is adjusted by using dilute caustic solution and the layers are separated. The solvent is distilled off and treated with IPA-HCl to give methylphenidate hydrochloride.
PCT application no. 2012/080834 discloses the process for preparing methylphenidate hydrochloride by treating dl-threo ritalinic acid which may be very pure material, with HCl gas in methanol. The reaction mixture is maintained for 20 hours at 41-42° C. Trimethyl orthoformate is added into the reaction mixture in one portion, maintained for 3.5 hours at 41-42° C. and 19 hours at room temperature. The reaction mixture is distilled off and isopropanol is added simultaneously. Subsequently the reaction mixture is cooled to 2° C. for 30 minutes to get methylphenidate hydrochloride. The reagent trimethyl orthophosphate is showing hazards like acute toxicity (oral, dermal, inhalation), skin irritation, eye irritation, skin sensitization and flammable as well. Moreover that use of additional regent like trimethyl orthophosphate in high quantity i.e 2 mole equivalents for the esterification will increase the cost of the product and hazardous for the environment as well as humans. The major negative point of trimethyl orthophosphate is effluent problem; hence it is not preferable for large scale.
A major drawback of the processes described in above documents is that they all use costly catalyst such as platinum metal adsorbed on carbon or platinum oxide with a very high loading [high loading means higher amounts with respect to the starting compound (II)] for the selective reduction of pyridine ring. Platinum catalysts are known for their high catalytic activity in comparison with milder metal catalyst such as Nickel or Palladium. The order of catalytic activity is Rh>Pt>Pd>Ni. By using Pt or its oxide and Rh catalyst for hydrogenation makes the process uneconomical. Other prior art process involves reduction of pyridine ring by using palladium catalyst with harsh and hazardous reagents, additional solvents, high pressure, lengthy and high cost equipments required, which cumulatively makes the process unattractive for industrial scale.
A need exists for a more efficient and economical process for the reduction of the pyridine ring and novel approach to prepare methylphenidate hydrochloride in good yield and high purity at industrial scale.
Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for reduction of pyridine ring of amide intermediate and/or the preparation of methylphenidate hydrochloride, which provides methylphenidate hydrochloride in high purity, overall good yield and one pot synthesis of methylphenidate hydrochloride from threo-2-phenyl-2-(piperidin-2-yl) acetamide [threo NLT 85%: erythro ˜12%]. The present invention can be described, as shown in scheme 2.
